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PubMed1988

Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa.

1. Gastric acid secretory responses to pentagastrin were characterized in the rat isolated gastric mucosa. In particular, the mechanisms underlying fade, declining response upon continued stimulation, and tachyphylaxis, progressively reduced responses upon repeated stimulation, were investigated. 2. Pentagastrin, 10(-9)-10(-7) M, resulted in concentration-related increases in acid secretion, with a mean maximum of 2.65 mumol cm-2 h-1 in response to pentagastrin, 10(-7) M. Higher concentrations of pentagastrin produced sub-maximal secretory rates; we define this as auto-inhibition. The responses to all concentrations of pentagastrin demonstrated fade. The rate of fade was correlated with the maximum acid secretory rate, declining at about 36% of the peak over the first 16 min. 3. The PO2, PCO2, [HCO3-], pH, [glucose], [lactate], [Na+] and [K+] did not decline during the fade of the acid secretory response to pentagastrin, 10(-7) M. Addition of a second aliquot of pentagastrin was not able to reverse fade, but these tissues were responsive to histamine. Replacement of the serosal solution, before addition of a second aliquot of pentagastrin, increased the acid response from 3% to 24% of the first response. 4. Serosal solution from donor tissues, allowed to respond to pentagastrin and then the acid secretion to fade, was able to stimulate secretion in fresh recipient tissues, although at lower rates. 5. Acid secretory responses to a second dose of pentagastrin were not significantly different, whether the tissues were previously unstimulated, or stimulated with pentagastrin washed out after attaining its peak secretory response (after 10-20 min). The second response was significantly reduced if the first response was allowed to fade with the pentagastrin in contact for 100 min; i.e. fade significantly influenced the extent of tachyphylaxis. 6. Proglumide, 10(-2) M, a gastrin receptor antagonist, and omeprazole, 10(-5) M, an inhibitor of the gastric (H+ + K+)-ATPase, both inhibited pentagastrin-stimulated acid secretion to similar extents. The second response to pentagastrin after pentagastrin alone, or pentagastrin plus omeprazole were both reduced compared to responses after no stimulation or omeprazole alone, respectively. After pentagastrin plus proglumide, the second response to pentagastrin was not lower than after proglumide alone. Proglumide, but not omeprazole, therefore, prevented pentagastrin tachyphylaxis. 7. It is concluded that gastrin fade and tachyphylaxis are related phenomena. Part of the fade may be due to release of an inhibitor(s). The major proportion of tachyphylaxis is a result of specific interaction of gastrin with its receptors.

Animals↗

PubMed1977

Specific desensitization (tachyphylaxis) of the guinea pig ileum to angiotensin II.

Tachyphylaxis to [Ile5]angiotensin II (angiotensin) in the isolated guinea pig ileum was found to be more severe when the Ca2+ concentration or the temperature of the medium were lowered, or when glucose was absent. Incubation with indomethacin or prostaglandin E2 did not affect the onset of tachyphylaxis or recovery from the tachyphylactic state. The angiotensin dose-response curves of tachyphylactic organs were shifted to the right, and the maximum responses were depressed in proportion to the conditioning doses of the hormone. The recovery from tachyphylaxis followed zero-order kinetics and was not affected by Ca2+ concentration or pH. The temperature dependence of the rate of recovery yielded a value of 14.6 kcal/mol for the activation energy in the physiological temperature range. It is concluded that tachyphylaxis results from the tight binding of angiotensin to superficial calcium-binding sites in the smooth muscle cell membrane. Recovery from tachyphylaxis appears to involve displacement of angiotensin by calcium in a process that is dependent on active transport.

Angiotensin II↗

PubMed1991

Increased intracellular Na+ and depolarization favor angiotension tachyphylaxis in rabbit aorta.

Tachyphylaxis to both angiotensin II (ANG II) and Sar1-ANG II is observed in normal rabbit aorta rings, but helical strips show tachyphylaxis only to Sar1-ANG II, whereas everted rings are not tachyphylactic to either analogue. In normal rings, a good correlation was observed between intraluminal pH and degree of tachyphylaxis to both analogues, suggesting that rate-limiting access of the agonists to their site of action may enhance tachyphylaxis in this preparation. Membrane potential and intracellular Na+ activity measurements, as well as the relaxation by K+ of norepinephrine-contracted preparations in K(+)-free medium, indicated that helical strips are more depolarized than everted rings due to Na+ leakage into the smooth muscle cells. These results suggest that the differences in the degree of tachyphylaxis induced by angiotensin in different rabbit aorta preparations are due to a less accessible site of action in normal rings and to the higher intracellular Na+ and more depolarized state of helical strips relative to everted rings.

Angiotensin II↗

PubMed1993

Tachyphylaxis to the vasopressor effects of endothelin in rat aortic rings.

Endothelin-1 (ET-1), a potent vasoconstrictor peptide released by endothelial cells, binds with high affinity to surface receptors and is highly resistant to dissociation. We observed tachyphylaxis to the pressor effects of a second application of ET-1 in rat aortic rings and investigated the mechanism of this effect. Developed tension increased progressively with doses of ET-1 ranging from 1 to 500 nM (P < 0.001), and tensions with rechallenge were correspondingly decreased (P < 0.001). In response to 500 nM ET-1, tension increased 1,599 +/- 72 (SE) mg/mg ring wt. Rechallenge with 500 nM ET-1 led to contraction of only 33 +/- 40 mg/mg ring wt. Tachyphylaxis was seen up to 6 h after initial challenge. Pretreatment with nicardipine, lidoflazine, nitroglycerin, and sphingosine did not affect tachyphylaxis. Pretreatment with 500 microM dansylcadaverine (an inhibitor of endothelin internalization) markedly inhibited ET-1-induced contraction and also inhibited tachyphylaxis to ET-1. Further studies with radiolabeled ET-1 suggested that subsequent ET-1 binding is markedly decreased after an initial ET-1 challenge. Dansylcadaverine inhibited ET-1 internalization and also inhibited the decreased binding seen with ET-1 rechallenge. Rat aortic rings demonstrate tachyphylaxis to the pressor effect of a second dose of ET-1. The mechanism appears to be related to binding and subsequent internalization of endothelin-receptor complexes. This effect suggests a possible mechanism for sustained decreases in systemic vascular resistance.

Animals↗

PubMed1977

Further studies on the tachyphylaxis to DSCG. The effects of concentration and temperature.

The tachyphylaxis to DSCG's inhibition of anaphylactic histamine release has been demonstrated in passively sensitized rat lung fragments. The induction of tachyphylaxis appears to depend on the concentration of the drug and the length of pretreatment. Tachyphylaxis is relatively independent of the concentration of the second exposure to DSCG. The development of tachyphylaxis is highly temperature dependent; it can be prevented by cooling the tissues to 2-4 degrees C after a brief (30 sec) preincubation with DSCG. It is suggested that DSCG inhibits histamine release by binding to 'receptor' site(s). Once the site is occupied by DSCG, it is modified by a temperature-dependent process, thus losing the ability as a 'receptor' for inhibition of histamine release. The tachyphylaxis is the result of such a modification.

Animals↗

PubMedDate not supplied

On the mechanism of tachyphylaxis to histamine in guinea pig seminal vesicle.

Repeated administration of high concentrations (10 muglml and above) of histamine produce tachyphylaxis in the seminal vesicle of guinea pig. Acetylcholine partially restores the response to histamine after development of constant tachyphylactic response. No tachyphylaxis occurred (in few experiments) in which the preparation is atropinized. Prior eserinization potentiates the response to histamine. After development of tachyphylaxis to histamine, increasing doses of histamine fail to produce log dose increase in the response. The results suggest that tachyphylaxis to histamine involves, desensitization of the receptors and further, a decrease in the release of acetylcholine may also contribute to the development of tachyphylaxis.

Animals↗

PubMedDate not supplied

Histamine tachyphylaxis in young dog airway--compared with adult dog.

The phenomenon of histamine tachyphylaxis in vitro previously observed in the airway smooth muscle from adult dogs was investigated in airway smooth muscle from young dogs (age 72-96 days; mean: 91 days). Tachyphylaxis was demonstrated by repetitive exposure to 10(-4) M histamine (4th contractile response was 53.0 +/- 4.9% of the initial histamine contraction; n = 6, P less than 0.01). This result was similar to that previously reported (Anderson et al., 1979) in adult canine tracheal smooth muscle. Tachyphylaxis to histamine was demonstrated also by repetitive exposure to histamine (10(-4) M) in the small airway smooth muscle (2 mm diameter), (4th contractile response was 59.6 +/- 7.2% of the initial histamine contraction; n = 6, P less than 0.01). This tachyphylaxic response is not present in the small airways from adult animals. The development of histamine tachyphylaxis in both tracheal and small airway smooth muscle could be prevented or reversed by preincubation of the tissue with indomethacin (2.8 x 10(-6) M). The composite information thus implicates prostaglandins as the most probable mediators of the process. These results suggest that the variable phenomenon of histamine tachyphylaxis is dependent on the maturity of the animal and on the size of the airway.

Aging↗

PubMed1977

Tachyphylaxis to the hypotensive effect of clonidine and the possible mechanism of this action.

In cats under chloralose-urethan anaesthesia, tachyphylaxis developed to the hypotensive effect of clonidine. Development of this tachyphylaxis was slow in the case of intravenous low doses (10--20 micrograms/kg) and rapid after high doses (50 micrograms/kg). No tachyphylaxis developed to contractions of the nictitating membrane. The phenomenon resembles the tachyphyaxis seen after the application of indirect sympathomimetics. A tachyphylaxis developed to the latter agents inhibited the hypotensive action of clonidine which, after such an intervention, invariably turned into a vasopressor effect. Clonidine exhibited the same behaviour after pretreatment with cocaine, bretylium or reserpine. Infusion of noradrenaline (10 micrograms/kg/min) counteracted the tachyphylaxis. Thus, clonidine is assumed to exert its hypotensive effect in an indirect way, i.e. by interference with the metabolism of noradrenaline.

Amphetamine↗

PubMed1995

Challenge interval determines tachyphylaxis to aerosolized LTD4.

Leukotrienes (LK) play an important role in the inflammatory response found in the asthmatic airway and it is therefore of interest to explore the clinical value of agents which can either block the effect or inhibit the synthesis of leukotrienes. If tachyphylaxis does not develop, repeated LTD4 challenges can be used for dose ranging studies. Tachyphylaxis has been observed when LTD4 challenge intervals are kept below 1 h, but the effect of prolonging the interval is uncertain. The aim of this study was therefore to investigate the interval between LTD4 challenges necessary to avoid development of tachyphylaxis. Ten stable adult asthmatics with moderate asthma were challenged seven times: a screening day to secure responsiveness to LTD4, two challenges on three separate days with an interval of 2, 4 and 6 h, respectively. No significant differences between mean PC20-LTD4 values (P > 0.5) was found. It was concluded that tachyphylaxis to repeated LTD4 challenges of asthmatics does not develop when challenge intervals are prolonged above 2 h.

Administration, Inhalation↗

PubMed1993

Role of Na+ and protein kinase C in angiotensin desensitization and tachyphylaxis in the guinea-pig ileum.

Simultaneous recordings of the tension and intracellular Ca2+ concentration of guinea-pig ileum longitudinal smooth muscle strips, as well as 24Na+ and 45Ca2+ influx measurements in cultured myocytes from the same tissue, were used to investigate the mechanisms underlying angiotensin-induced desensitization and tachyphylaxis. Angiotensin II and [2-lysine]-angiotensin II (Lys2All), incubated for prolonged periods (10 min) with muscle strips, induced fading of the contractile response (desensitization) and reappearance of the intracellular Ca2+ concentration oscillations, which were inhibited during the initial increase in cytosolic Ca2+. The desensitization was paralleled, in cultured myocytes, by inhibition of the 45Ca2+ but not of the 24Na+ influxes which were initially stimulated by the peptides. On the other hand, repeated administrations of angiotensin II (but not of Lys2All) caused gradual reduction of the contractile response and of the 24Na+ influx stimulation evoked by the agonist (tachyphylaxis). Treatment with phorbol 12-13 dibutyrate accelerated the desensitization induced by both angiotensin II and by Lys2All and aggravated the tachyphylaxis to angiotensin II. The results support the hypothesis that activation of protein kinase C is responsible for the desensitization and that tachyphylaxis is due to the slow dissociation of angiotensin II from a postulated Na(+)-dependent regulatory site on the receptor.

Angiotensin II↗

PubMed1977

Tachyphylaxis to beta-adrenoceptor agonists in guinea pig airway smooth muscle in vivo and in vitro.

Beta-Adrenoceptor tachyphylaxis was induced by incubating spirally cut guinea pig tracheas with isoproterenol (2.4 x 10(-7) M) for 20 min. This incubation reduced the relaxant effects of catecholamines but not of dibutyryl cyclic AMP, theophylline or sodium nitrite. Tracheas incubated with norepinephrine, phosphodiesterase inhibitors or cyclic nucleotides became tachyphylactic to isoproterenol. Pretreatment with indomethacin prevented induction of tachyphylaxis. Incubation with adenosine, methoxamine or sodium nitrite did not induce beta-adrenoceptor tachyphylaxis. When we gave isoproterenol intramuscularly to guinea pigs, airway sensitivity to aerosolized histamine was unchanged but the toxicity of parenterally administered histamine was increased. A prolonged treatment with isoproterenol reduced airway sensitivity to histamine aerosols; this reduced sensitivity was reversed by indomethacin. Thus, beta-adrenoceptor tachyphylaxis may not explain increased toxicity of parenteral histamine after isoproterenol treatment. Elevated levels of cyclic AMP and an increased synthesis of prostaglandins may result in diminished response to beta-receptor stimulation.

Adrenergic beta-Agonists↗

PubMed1987

Endothelium enhances tachyphylaxis to angiotensins II and III in rat aorta.

Development of tachyphylaxis to angiotensin-induced contraction was compared in rings of rat aorta with and without functional endothelium. Rat aorta with functional endothelium rapidly developed marked tachyphylaxis to contraction induced by angiotensin II or angiotensin III. Destruction of endothelium significantly depressed, but did not prevent, development of tachyphylaxis to contractile responses induced by repeated exposure to angiotensin II or angiotensin III. The findings suggest that two mechanisms are involved in the development of tachyphylaxis to angiotensin in rat aorta, an endothelium-dependent mechanism and an endothelium-independent mechanism.

Angiotensin II↗

PubMed1988

The mucosa mediates tachyphylaxis to leukotrienes C4, D4 and E4 in guinea pig trachea.

Effects of mucosal abrasion on tracheal smooth muscle leukotriene C4, D4 and E4 tachyphylaxis and on histamine contractions before and after four leukotriene exposures were studied. In intact tracheae, leukotriene C4 and E4 second exposure contractions were greater than first. Subsequent contractions showed tachyphylaxis. Leukotriene D4 contractions exhibited progressive tachyphylaxis. Mucosal abrasion potentiated initial leukotriene C4 and D contractions and eliminated leukotriene C4, D4 and E4 tachyphylaxis. Four leukotriene (10(-8) M) exposures reduced histamine (10(-4) M) responses in intact but not abraded preparations. Thus leukotriene C4, D4 and E4 release non-specific inhibitor(s) from tracheal mucosa.

Animals↗

PubMed1993

Angiotensin II-induced tachyphylaxis in aortas of normo- and hypertensive rats: changes in receptor affinity.

Angiotensin II-induced tachyphylaxis was found to be associated with changes in agonist affinity (Ka) and EC50 values, as assessed by using Furchgott's equation derived for the determination of full agonist affinity. The diminished affinity during tachyphylaxis was observed in aorta ring preparations from both Wistar-Kyoto and spontaneously hypertensive rats. Noradrenaline (10(-9) M) reduced the increase in the Ka value during tachyphylaxis in both strains. The results suggest that tachyphylaxis occurs at the level of the receptor, resulting in changes in the affinity of the ligand for the receptor and in the coupling efficiency of the receptor system. The results also support the probable role of modulators acting on allosteric receptor sites.

Angiotensin II↗

PubMed1994

Modulation of tachyphylaxis to angiotensin II in rabbit isolated aorta by the angiotensin AT1 receptor antagonist, losartan.

In rabbit aortic strip preparations, angiotensin II (AII) concentration-contractile response curves (0.3-100 nM) were highly reproducible. However, tachyphylaxis to the contractile response elicited by AII could be induced by repeated exposure to a supramaximal concentration (10 microM) of the peptide. In contrast, a correspondingly supramaximal concentration of the alpha 1-adrenoceptor agonist, phenylephrine (1 mM), did not cause the tissue to become tachyphylactic to phenylephrine. Furthermore, phenylephrine responses were unaffected in tissues previously made tachyphylactic to AII. When the non-peptide, competitive angiotensin AT1 receptor antagonist, losartan (300 nM), was administered before each supramaximal AII challenge, tachyphylaxis did not subsequently occur. Additionally, in tissues made tachyphylactic to AII, subsequent incubation with losartan (300 nM) reversed the AII tachyphylaxis. Thus, losartan may prevent the loss of contractility by preventing AII from interacting with its receptor in a manner which induces tachyphylaxis. However, since losartan can also completely reverse the loss of contractility, it appears capable of restoring the AT1 receptor to a state which allows subsequently administered AII to fully activate the contractile pathway.

Angiotensin II↗

PubMed2006

Tachyphylaxis to 5-HT3-receptor-mediated activation of vagal afferents is prevented by co-activation of 5-HT2 receptors.

Functional studies have provided evidence that 5-HT(3) ion-channel receptors (5-HT(3)Rs) on vagal cardiopulmonary afferents mediating the Bezold-Jarisch reflex (BJR) rapidly desensitize upon repeated exposure to selective 5-HT(3)R agonists. G-protein-coupled 5-HT(2) receptors (5-HT(2)Rs) also exist on vagal afferents, although activation of these receptors does not elicit the BJR. However, there is in vivo evidence that 5-HT(2)Rs may regulate the activity of 5-HT(3)Rs. The aim of this study was to determine whether co-activation of 5-HT(2)Rs prevents desensitization of 5-HT(3)Rs mediating the BJR in conscious rats. The principal findings were that (1) tachyphylaxis rapidly developed to the BJR-mediated hemodynamic responses elicited by successive injections of 5-HT(3)R agonists and (2) co-injection of the selective 5-HT(2)R agonist, alpha-methyl-5-HT, prevented tachyphylaxis to the BJR-mediated hemodynamic responses elicited by the 5-HT(3)R agonists. Additional studies provided evidence that (1) tachyphylaxis to the 5-HT(3)R agonists was not due to impairment of the central or efferent processing of the BJR, and (2) the pressor responses elicited by alpha-methyl-5-HT were not responsible for preventing tachyphylaxis to the BJR reflex responses elicited by 5-HT(3)R agonists. These results suggest that the loss of response to 5-HT(3)R agonists is due to desensitization of 5-HT(3)Rs on vagal afferents mediating the BJR and that co-activation of 5-HT(2)Rs prevents the desensitization of these 5-HT(3)Rs.

Animals↗

PubMed2000

Development of tachyphylaxis among patients taking HMG CoA reductase inhibitors.

The purpose of this study was to determine if long-term use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin) resulted in tachyphylaxis (a decreasing response to a physiologically active agent). To determine this, the charts of 254 patients treated with statins from the years 1996 to 1998 were retrospectively reviewed. During treatment, the low-density lipoprotein (LDL) cholesterol levels of patients were followed for a minimum of 300 days. To characterize LDL cholesterol changes during statin therapy, linear and nonlinear kinetic models were generated. Tachyphylaxis, defined as a positive slope of LDL cholesterol over time, after maximum LDL cholesterol reduction, was identified in patients treated with atorvastatin at exposure doses of 10 or 20 mg/day. All other statins, at all doses reviewed, showed no [corrected] evidence of tachyphylaxis. LDL cholesterol tachyphylaxis appeared to be a unique response to prolonged use of long half-life atorvastatin therapy at exposure dosages.

Atorvastatin↗

PubMed2001

Administration of myr(+)-G(i2)alpha subunits prevents acute tolerance (tachyphylaxis) to mu-opioid effects in mice.

The administration of efficacious doses of morphine or beta-endorphin causes acute tolerance (tachyphylaxis) to the effects of additional administrations of these opioids. Mice intracerebroventricularly (icv)-injected with biologically active myristoylated (myr(+))-G(i2)alpha subunits developed no tachyphylaxis to morphine antinociception in the tail-flick test. This treatment increased the potency of opioid-induced analgesia during the declining phase. Moreover, animals showing tachyphylaxis to opioid effects exhibited normal responses to the agonists after icv-administration of myr(+)-G(i2)alpha subunits. In morphine tolerant/dependent mice, an icv dose of 12 pmol/mouse myr(+)-G(i2)alpha subunits facilitated complete restoration of morphine antinociception in only 4 or 5 days instead of the 10 to 11 days required for post-dependent mice. This was observed when myr(+)-G alpha subunits were injected within the first 24 h of chronic morphine administration -- but not later when long-term tolerance takes place. These results suggest that during the course of an opioid effect a progressive reduction of receptor-regulated G-proteins occurs, and hence tachyphylaxis develops. Exogenous administration of myr(+)-G alpha subunits may be of therapeutic potential in improving agonist activity and accelerating the recovery of post-dependent receptors.

Analgesics, Opioid↗